Alternative titles; symbols
HGNC Approved Gene Symbol: PDE6B
Cytogenetic location: 4p16.3 Genomic coordinates (GRCh38): 4:625,573-670,782 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4p16.3 | Night blindness, congenital stationary, autosomal dominant 2 | 163500 | Autosomal dominant | 3 |
| Retinitis pigmentosa-40 | 613801 | Autosomal recessive | 3 |
Absorption of a photon by rhodopsin (180380) triggers visual signaling in rod photoreceptors. The phototransduction cascade leads to rapid hydrolysis of cGMP by activated cGMP phosphodiesterase (PDE), resulting in closure of cGMP-gated cation channels in the plasma membrane and hyperpolarization of the cell. Rod PDE is a peripheral membrane heterotrimeric enzyme made up of alpha (PDE6A; 180071), beta (PDE6B), and gamma (PDE6G; 180073) subunits (Khramtsov et al., 1993).
Using the bovine PDE beta subunit as probe, Khramtsov et al. (1993) cloned human PDE6B from a retina cDNA library. The deduced 854-amino acid protein has a calculated molecular mass of 98.4 kD. It has an N-terminal internal repeat that may be a noncatalytic cGMP-binding site and a C-terminal 250-residue catalytic domain for cyclic nucleotide hydrolysis that includes conserved elements for binding guanine nucleotides and magnesium. PDE6B also has a C-terminal CAAX motif for posttranslational processing involving lipidation, proteolysis, and carboxymethylation. Human PDE6B shares 91.1% and 92.4% amino acid identity with bovine and mouse PDE beta subunits, respectively. A Pde6b splice variant in mouse encodes a truncated isoform, but Khramtsov et al. (1993) found no homologous splice variant of human PDE6B.
By sequence analysis of mouse and human PDE6B, Khramtsov et al. (1993) determined that the human PDE6B gene contains 22 exons.
Weber et al. (1991) showed that the PDEB gene is located in the most distal region of a 460-kb cosmid contig close to the 4p telomere. Physical mapping data obtained from pulsed field gel electrophoresis analysis with 3 probes allowed the construction of a physical long-range map of approximately 720 kb that extended to the 4p telomere. They concluded that the PDEB gene is located approximately 650 to 700 kb proximal to the 4p telomere and represented to date the most telomeric gene characterized on 4p.
Bateman et al. (1992) mapped the PDEB gene to human chromosome 4 by use of somatic cell hybrids and further localized it to 4p16 by in situ hybridization. Altherr et al. (1992) narrowed the assignment to the most distal subband of chromosome 4, p16.3, by Southern blot hybridization to DNAs from 8 cell hybrids defining 9 distinct regions of chromosome 4. The p16.3 region contains several DNA markers closely linked to the gene for Huntington disease (HD; 143100). From studies of the comparative mapping of this region in man and mouse, Altherr et al. (1992) concluded that the homolog of the HD gene should be located on mouse chromosome 5, where Pdeb is located. Indeed, PDEB was a plausible candidate gene for HD based on its expression in brain, the demonstration of linkage disequilibrium between intragenic DNA markers and HD, and the demonstration that mice with a mutation in this gene have a reduction of neurons in particular brain regions.
In a report of the fourth international workshop on human chromosome 4 mapping, Riess et al. (1996) presented a physical map of 4p16.3. The location of disease-related genes relative to the telomere placed PDEB most distal, followed by IDUA (Hurler syndrome), FGFR3 (achondroplasia), and Huntington disease, the last being closest to the centromere.
Retinitis Pigmentosa 40
In affected members of several families with retinitis pigmentosa-40 (RP40; 613801), McLaughlin et al. (1993) identified homozygous or compound heterozygous mutations in the PDE6B gene (see, e.g., 180072.0001-180072.0004).
Congenital Stationary Night Blindness, Autosomal Dominant 2
In affected members of a large 11-generation Danish family, referred to as the Rambusch pedigree, segregating autosomal dominant congenital stationary night blindness mapping to chromosome 4p16.3 (CSNBAD2; 163500), Gal et al. (1994) identified a heterozygous missense mutation in the PDE6B gene (H258N; 180072.0005) that segregated fully with disease. The authors hypothesized that the mutation impeded complete inactivation of phosphodiesterase in dark-adapted photoreceptors, thus resulting in CSNB.
In a 36-year-old man with a long history of night blindness and myopia, Tsang et al. (2007) identified heterozygosity for the previously reported H258N mutation in the PDE6B gene. Mutation status of family members was not reported. The authors noted that considerable phenotypic variability in residual rod activity had been reported in affected members of the Rambusch pedigree, and suggested that factors other than the PDE6B gene itself might contribute to the pathophysiology of the retinal dystrophy.
Mice homozygous for the rd mutation display hereditary retinal degeneration and have been considered a model for human retinitis pigmentosa. In affected animals, the retinal rod photoreceptor cells begin degenerating at about postnatal day 8, and by 4 weeks no photoreceptors are left. Farber and Lolley (1974, 1976) showed that degeneration was preceded by accumulation of cyclic GMP in the retina and was correlated with deficient activity of the rod photoreceptor cGMP-phosphodiesterase. Sidman and Green (1965) mapped the murine rd locus to chromosome 5.
Keeler (1924) first described the 'rodless retina' mutation (gene symbol, r), but mice carrying the mutation were lost by the end of World War II. Mice with a similar retinal phenotype were recognized in Basel in the early 1950s. Studies of these mice led to the conclusion that a different mutation, later called 'retinal degeneration' (rd), was involved. Pittler et al. (1993) used PCR to recover DNA from 70-year-old histologic sections of r/r eyes. They found the same nonsense mutation and intronic polymorphisms that were present in rd strains to be present in the DNA of the mice identified by Keeler (1924). Because of the extensive use of the name in publications of the past 40 years, Pittler et al. (1993) proposed that the gene continue to be designated 'retinal degeneration' (rd). Thus, the inherited defect that was first recognized more than 70 years ago has now been shown to be caused by a defective Pdeb gene carrying both an intronic transcriptionally active MLV virus insertion and a nonsense mutation. That this pair of mutations is widely distributed through inbred strains and recently captured wild mouse strains from different parts of the world suggests a very ancient history for rd. See Howard (1995) for a biography of Clyde Edgar Keeler (1900-1994).
Bennett et al. (1996) tested the possibility of altering the course of retinal degeneration through subretinal injection of recombinant replication defective adenovirus that contained the murine cDNA for wildtype beta-PDE. Subretinal injection of rd mice was carried out 4 days after birth, before the onset of rd retinal degeneration. Following therapy, beta-PDE transcripts and enzyme activity were detected, and histologic studies revealed that photoreceptor cell death was significantly retarded.
Van Gelder et al. (2003) tested pupillary light responses of cryptochrome mutant mice (Cry1 -/-; Cry2 -/-), rd/rd mice, and mice mutant for all of these loci, as well littermate controls. There was substantial loss of constriction in rd/rd mice compared with control mice. The double mutants for the cryptochromes showed a pupillary response similar in magnitude to that in control mice. Almost no pupillary constriction was observed in the triple knockouts at a 470-nm light intensity. Pupillary responses of the triple mutants were about 5% as sensitive to blue light as those of the rd/rd mice. Some pupillary responses were retained in the triple mutant mice under very bright light, although pupillary movement was somewhat sluggish. The 50% constriction threshold of pupillary responses was noted in Cry1 -/-;rd/rd and Cry2 -/-;rd/rd mice, and was comparable to those of rd/rd mice, indicating that either Cry1 or Cry2 function is sufficient for retention of pupillary responses in rd/rd animals. Since all mice were of the same strain background, strain differences were unlikely to account for the observed differences in pupillary light responses. Van Gelder et al. (2003) suggested that murine cryptochromes may function as inner retinal photopigments.
Zeiss et al. (2004) evaluated the impact of caspase-3 (CASP3; 600636) ablation on photoreceptor degeneration and studied its role in postnatal retinal development in the rd mouse. They found that Casp3-deficient mice displayed marginal microphthalmia, peripapillary retinal dysplasia, delayed regression of vitreal vasculature, and retarded apoptotic kinetics of the inner nuclear layer. Although ablation of caspase-3 provided transient photoreceptor protection, rod death proceeded. Zeiss et al. (2004) concluded that in vivo, caspase-3 is not critical for rod photoreceptor development, nor does it play a significant role in mediating pathologic rod death. The temporal nature of apoptotic retardation in the absence of caspase-3 implied the presence of caspase-independent mechanisms of developmental and pathologic cell death.
In a study of cell cycle progression in the retina of the rd mouse, Zeiss and Johnson (2004) found that a population of proliferating cells in the outer nuclear layer accompanied photoreceptor death; however, cell cycle progression in the photoreceptors could not be demonstrated. Zeiss and Johnson (2004) concluded that in the rd mouse evidence of photoreceptor cell cycle progression in rd retinas exposed to neurotrophic factors is likely to result from the therapy itself. In addition, the results confirmed that proliferating microglial cells are intimately associated with the degenerative process in rd.
Using a mouse model of RP in which rod photoreceptors contain a mutated Pde6b gene (rd10), Zhao et al. (2015) discovered that resident immune cells in the retina, microglia, play a role in potentiating the rate of rod photoreceptor death via phagocytic and proinflammatory mechanisms. Microglia responded to mutations in photoreceptors by infiltrating the outer retina and dynamically contacting mutated rods via motile processes. Microglia contributed directly to rod demise by rapid phagocytic engulfment of nonapoptotic rods, increasing the rate of rod degeneration. Activated microglia also increased rod apoptosis by the production of the proinflammatory cytokine interleukin-1-beta IL1B (147720). Genetic ablation of retinal microglia, pharmacologic inhibition of microglia phagocytosis, and inhibition of IL1B signaling, all slowed down rod degeneration, demonstrating the non-cell-autonomous contribution that microglia make to photoreceptor degeneration in RP.
In the rd1 mouse model and in an in vitro cellular model, Sanges et al. (2006) found that both Aif (AIFM1; 300169) and caspase-12 (CASP12; 608633) translocated to the nucleus of dying photoreceptors. Only differentiated rd1 photoreceptors underwent apoptosis, and apoptosis was never observed in amacrine, bipolar, or horizontal retinal neurons. Translocation of both apoptotic factors required increased intracellular calcium, and calpain (see CAPN1; 114220) inhibitors interfered with Aif and Casp12 activation and rd1 photoreceptor apoptosis. Knockdown of Aif or Casp12 by interfering RNA showed that Aif played a major role in this apoptotic event and that Casp12 had a reinforcing effect.
Canola et al. (2007) transplanted retinal stem cells into the eyes of mouse models of late stage RP, including rd1, and found that the grafted cells preferentially integrated into the ganglion cell layer and inner plexiform layer and expressed ganglion cell or glial markers. Few grafted cells stayed in the degenerating outer nuclear layer. The authors suggested that a predifferentiation of retinal stem cells into photoreceptors before transplantation might be necessary to obtain graft integration in the outer nuclear layer.
Thaung et al. (2002) carried out a genomewide screen for novel N-ethyl-N-nitrosourea-induced mutations that give rise to eye and vision abnormalities in the mouse, and identified 25 inherited phenotypes that affect all parts of the eye. A combination of genetic mapping, complementation, and molecular analysis revealed that 14 of these were mutations in genes previously identified to play a role in eye pathophysiology, namely Pax6 (607108), Mitf (156845), Egfr (131550), and Pde6b. Many of the others were located in genomic regions lacking candidate genes.
Rod-cone dysplasia-1 (rcd1) in Irish setters is caused by a nonsense mutation in the PDE6B gene (Clements et al., 1993; Suber et al., 1993). A G-to-A transition at nucleotide 2420 of the PDE6B cDNA is predicted to cause premature termination of the protein by 49 amino acid residues. Identification of the same mutation in the United Kingdom and America suggests a founder effect. In a voluntary testing program sponsored by the Irish Setter Club of America, samples were obtained between 1994 and 1997 from 436 clinically normal Irish setters, a red wolf, and dogs from 23 different breeds (Aguirre et al., 1999). The mutation in codon 807 was detected in genomic DNA from 34 of the 436 samples from clinically normal setters (heterozygote carrier rate = 7.8%). In contrast, the same mutation was not found in the red wolf or dogs of other breeds, all of whom were tested because of the presence of primary retinal atrophy (PRA) or inherited photoreceptor diseases.
In 2 sibs with autosomal recessive retinitis pigmentosa (RP40; 613801), McLaughlin et al. (1993) found compound heterozygosity for a gln298-to-ter (Q298X) mutation and an arg531-to-ter mutation (R531X; 180072.0002) in the PDE6B gene. The patients reported absent night vision since early childhood. Ophthalmoscopy showed attenuated retinal vessels and typical intraretinal bone-spicule pigment around the midperiphery. Rod and cone electroretinograms were abnormal. SSCP analysis was used in detecting mutations. The Q298X mutation resulted from a C-to-T transition at position 11638 in exon 5; the R531X mutation resulted from a C-to-T transition at position 18086 in exon 12.
For discussion of the arg531-to-ter (R531X) mutation in the PDE6B gene that was found in compound heterozygous state in patients with retinitis pigmentosa (RP40; 613801) by McLaughlin et al. (1993), see 180072.0001.
In a patient with autosomal recessive retinitis pigmentosa (RP40; 613801), McLaughlin et al. (1993) identified a 1-bp deletion at position 17981 in exon 12 of the PDE6B gene involving the codon for proline-496.
Using SSCP analysis to study DNA from a patient with autosomal recessive retinitis pigmentosa (RP40; 613801), McLaughlin et al. (1993) identified a C-to-T transition at position 19876 in exon 13 of the PDE6B gene, resulting in a his557-to-tyr (H557Y) substitution.
In a large Danish kindred with congenital stationary night blindness (CSNBAD2; 163500) first described by H. S. A. Rambusch in 1909, Gal et al. (1994) identified a heterozygous C-to-A transversion in exon 4 of the PDE6B gene in affected members of the kindred. The nucleotide substitution predicted a his258-to-asn (H258N) change in the polypeptide.
In a 36-year-old man with congenital stationary night blindness and the H258N mutation, Tsang et al. (2007) reported generalized retinal dysfunction affecting the rod system and a locus of dysfunction at the rod-bipolar interface. There was little change in 10 years and no evidence of photoreceptor cell death.
Tsang et al. (2007) found that rd1/rd1 mice displayed photoreceptor degeneration, whereas transgenic H258N mice displayed normal photoreceptor morphology. H258N/rd1 backcross rescued the photoreceptor degeneration associated with rd1. The cGMP-PDE6 activity of dark-adapted H258N mice showed an approximate 3-fold increase in the rate of retinal cGMP hydrolysis compared to controls, consistent with the hypothesis that inhibition of PDE6B activity by the regulatory PDE6G subunit (180073) is blocked by the H258N mutation.
In a study of 19 families with autosomal recessive retinitis pigmentosa in Spain, Bayes et al. (1995) found that involvement of the PDE6B gene was excluded in all but 1. In this family (RP40; 613801), a consanguineous pedigree, they found a homozygous 71-bp tandem duplication in exon 1 of the affected member, while each parent was heterozygous. The defect caused a frameshift that led to a premature stop codon. In general, the findings of Bayes et al. (1995) suggest that mutations in the PDE6B gene may be responsible for only about 5% of cases of autosomal recessive RP.
In affected members of a large consanguineous Tunisian family with autosomal recessive retinitis pigmentosa (RP40; 613801), Hmani-Aifa et al. (2009) identified a homozygous 2419T-A transversion in exon 21 of the PDE6B gene, resulting in a trp807-to-arg (W807R) substitution. Heterozygous mutation carriers were unaffected. The family also segregated Usher syndrome-2C (605472) associated with a homozygous mutation in the GPR98 gene (602851.0006). One family member who was doubly homozygous for both mutations had a more severe ocular phenotype. Two family members who were doubly heterozygous for both mutations were unaffected at ages 82 and 65 years, respectively. Hmani-Aifa et al. (2009) commented that consanguinity can increase familial clustering of multiple hereditary diseases within the same family. The family had originally been reported by Hmani et al. (1999).
By next-generation sequencing in 1 of 2 Spanish sibs (family S23) with retinitis pigmentosa (RP40; 613801), previously reported by Bernal et al. (2003), Pozo et al. (2015) identified a homozygous c.1678C-T transition in exon 16 of the PDE6B gene, resulting in an arg560-to-cys (R560C) substitution at a conserved residue in a domain responsible for the catalytic function of the protein. The mutation segregated with the disease in the family and was absent in 200 control individuals. The authors noted that an R560C mutation was previously identified in the Pde6b-rd10 mutant mouse by Chang et al. (2007). In the S23 family, Bernal et al. (2003) had identified a homozygous mutation in the USH2A gene (C759F; 608400.0006) in the 2 affected sibs as well as in 2 of their unaffected sibs, indicating that the C759F mutation was not causative.
Aguirre, G. D., Baldwin, V., Weeks, K. M., Acland, G. M., Ray, K. Frequency of the codon 807 mutation in the cGMP phosphodiesterase beta-subunit gene in Irish setters and other dog breeds with hereditary retinal degeneration. J. Hered. 90: 143-147, 1999. [PubMed: 9987922] [Full Text: https://doi.org/10.1093/jhered/90.1.143]
Altherr, M. R., Wasmuth, J. J., Seldin, M. F., Nadeau, J. H., Baehr, W., Pittler, S. J. Chromosome mapping of the rod photoreceptor cGMP phosphodiesterase beta-subunit gene in mouse and human: tight linkage to the Huntington disease region (4p16.3). Genomics 12: 750-754, 1992. [PubMed: 1315306] [Full Text: https://doi.org/10.1016/0888-7543(92)90305-c]
Bateman, J. B., Klisak, I., Kojis, T., Mohandas, T., Sparkes, R. S., Li, T., Applebury, M. L., Bowes, C., Farber, D. B. Assignment of the beta-subunit of rod photoreceptor cGMP phosphodiesterase gene PDEB (homolog of the mouse rd gene) to human chromosome 4p16. Genomics 12: 601-603, 1992. [PubMed: 1313787] [Full Text: https://doi.org/10.1016/0888-7543(92)90454-z]
Bayes, M., Giordano, M., Balcells, S., Grinberg, D., Vilageliu, L., Martinez, I., Ayuso, C., Benitez, J., Ramos-Arroyo, M. A., Chivelet, P., Solans, T., Valverde, D., Amselem, S., Goossens, M., Baiget, M., Gonzalez-Duarte, R., Besmond, C. Homozygous tandem duplication within the gene encoding the beta-subunit of rod phosphodiesterase as a cause for autosomal recessive retinitis pigmentosa. Hum. Mutat. 5: 228-234, 1995. [PubMed: 7599633] [Full Text: https://doi.org/10.1002/humu.1380050307]
Bennett, J., Tanabe, T., Sun, D., Zeng, Y., Kjeldbye, H., Gouras, P., Maguire, A. M. Photoreceptor cell rescue in retinal degeneration (rd) mice by in vivo gene therapy. Nature Med. 2: 649, 1996. [PubMed: 8640555] [Full Text: https://doi.org/10.1038/nm0696-649]
Bernal, S., Ayuso, C., Antinolo, G., Gimenez, A., Borrego, S., Trujillo, M. J., Marcos, I., Calaf, M., Del Rio, E., Baiget, M. Mutations in USH2A in Spanish patients with autosomal recessive retinitis pigmentosa: high prevalence and phenotypic variation. J. Med. Genet. 40: e8, 2003. Note: Electronic Article. [PubMed: 12525556] [Full Text: https://doi.org/10.1136/jmg.40.1.e8]
Bowes, C., Danciger, M., Kozak, C. A., Farber, D. B. Isolation of a candidate cDNA for the gene causing retinal degeneration in the rd mouse. Proc. Nat. Acad. Sci. 86: 9722-9726, 1989. Note: Erratum: Proc. Nat. Acad. Sci 87: 1625, 1990. [PubMed: 2481314] [Full Text: https://doi.org/10.1073/pnas.86.24.9722]
Bowes, C., Li, T., Danciger, M., Baxter, L. C., Applebury, M. L., Farber, D. B. Retinal degeneration in the rd mouse is caused by a defect in the beta subunit of rod cGMP-phosphodiesterase. Nature 347: 677-680, 1990. [PubMed: 1977087] [Full Text: https://doi.org/10.1038/347677a0]
Bowes, C., Li, T., Frankel, W. N., Danciger, M., Coffin, J. M., Applebury, M. L., Farber, D. B. Localization of a retroviral element within the rd gene coding for the beta subunit of cGMP phosphodiesterase. Proc. Nat. Acad. Sci. 90: 2955-2959, 1993. [PubMed: 8385352] [Full Text: https://doi.org/10.1073/pnas.90.7.2955]
Cachon-Gonzalez, M. B., Fenner, S., Coffin, J. M., Moran, C., Best, S., Stoye, J. P. Structure and expression of the hairless gene of mice. Proc. Nat. Acad. Sci. 91: 7717-7721, 1994. [PubMed: 8052649] [Full Text: https://doi.org/10.1073/pnas.91.16.7717]
Canola, K., Angenieux, B., Tekaya, M., Quiambao, A., Naash, M. I., Munier, F. L., Schorderet, D. F., Arsenijevic, Y. Retinal stem cells transplanted into models of late stages of retinitis pigmentosa preferentially adopt a glial or a retinal ganglion cell fate. Invest. Ophthal. Vis. Sci. 48: 446-454, 2007. [PubMed: 17197566] [Full Text: https://doi.org/10.1167/iovs.06-0190]
Chang, B., Hawes, N. L. Pardue, M. T., German, A. M., Hurd, R. E., Davisson, M. T., Nusinowitz, S., Rengarajan, K., Boyd, A. P., Sidney, S. S., Phillips, M. J., Stewart, R. E., Chaudhury, R., Nickerson, J. M., Heckenlively, J. R., Boatright, J. H. Two mouse retinal degenerations caused by missense mutations in the beta-subunit of rod cGMP phosphodiesterase gene. Vision Res. 47: 624-633, 2007. [PubMed: 17267005] [Full Text: https://doi.org/10.1016/j.visres.2006.11.020]
Clements, P. J. M., Gregory, C. Y., Peterson-Jones, S. M., Sargan, D. R., Bhattacharya, S. S. Confirmation of the rod cGMP phosphodiesterase beta subunit (PDE-beta) nonsense mutation in affected rcd-1 Irish setters in the UK and the development of a diagnostic test. Curr. Eye Res. 12: 861-866, 1993. [PubMed: 8261797] [Full Text: https://doi.org/10.3109/02713689309020391]
Collins, C., Hutchinson, G., Kowbel, D., Riess, O., Weber, B., Hayden, M. R. The human beta-subunit of rod photoreceptor cGMP phosphodiesterase: complete retinal cDNA sequence and evidence for expression in brain. Genomics 13: 698-704, 1992. [PubMed: 1322354] [Full Text: https://doi.org/10.1016/0888-7543(92)90144-h]
Danciger, M., Bowes, C., Kozak, C. A., LaVail, M. M., Farber, D. B. Fine mapping of a putative rd cDNA and its cosegregation with rd expression. Invest. Ophthal. Vis. Sci. 31: 1427-1432, 1990. [PubMed: 1974892]
Farber, D. B., Danciger, J. S., Aguirre, G. The beta subunit of cyclic GMP phosphodiesterase mRNA is deficient in canine rod-cone dysplasia 1. Neuron 9: 349-356, 1992. [PubMed: 1323314] [Full Text: https://doi.org/10.1016/0896-6273(92)90173-b]
Farber, D. B., Lolley, R. N. Cyclic guanosine monophosphate: elevation in degenerating photoreceptor cells of the C3H mouse retina. Science 186: 449-451, 1974. [PubMed: 4369896] [Full Text: https://doi.org/10.1126/science.186.4162.449]
Farber, D. B., Lolley, R. N. Enzyme basis for cyclic GMP accumulation in degenerative photoreceptor cells of mouse retina. J. Cyclic Nucleotide Res. 2: 139-148, 1976. [PubMed: 6493]
Gal, A., Orth, U., Baehr, W., Schwinger, E., Rosenberg, T. Heterozygous missense mutation in the rod cGMP phosphodiesterase beta-subunit gene in autosomal dominant stationary night blindness. Nature Genet. 7: 64-68, 1994. Note: Erratum: Nature Genet. 7: 551 only, 1994. [PubMed: 8075643] [Full Text: https://doi.org/10.1038/ng0594-64]
Gal, A., Xu, S., Piczenik, Y., Eiberg, H., Duvigneau, C., Schwinger, E., Rosenberg, T. Gene for autosomal dominant congenital stationary night blindness maps to the same region as the gene for the beta-subunit of the rod photoreceptor cGMP phosphodiesterase (PDEB) in chromosome 4p16.3. Hum. Molec. Genet. 3: 323-325, 1994. [PubMed: 8004102] [Full Text: https://doi.org/10.1093/hmg/3.2.323]
Harbers, K., Kuehn, M., Delius, H., Jaenisch, R. Insertion of retrovirus into the first intron of alpha 1 (I) collagen gene to embryonic lethal mutation in mice. Proc. Nat. Acad. Sci. 81: 1504-1508, 1984. [PubMed: 6324198] [Full Text: https://doi.org/10.1073/pnas.81.5.1504]
Hmani, M., Ghorbel, A., Boulila-Elgaied, A., Ben Zina, Z., Kammoun, W., Drira, M., Chaabouni, M., Petit, C., Ayadi, H. A novel locus for Usher syndrome type II, USH2B, maps to chromosome 3 at p23-24.2. Europ. J. Hum. Genet. 7: 363-367, 1999. [PubMed: 10234513] [Full Text: https://doi.org/10.1038/sj.ejhg.5200307]
Hmani-Aifa, M., Benzina, Z., Zulfiqar, F., Dhouib, H., Shahzadi, A., Ghorbel, A., Rebai, A., Soderkvist, P., Riazuddin, S., Kimberling, W. J., Ayadi, H. Identification of two new mutations in the GPR98 and the PDE6B genes segregating in a Tunisian family. Europ. J. Hum. Genet. 17: 474-482, 2009. [PubMed: 18854872] [Full Text: https://doi.org/10.1038/ejhg.2008.167]
Howard, I. K. Clyde Edgar Keeler (1900-1994): geneticist, artist, cultural historian. J. Hered. 86: 489-491, 1995.
Jenkins, N. A., Copeland, N. G., Taylor, B. A., Lee, B. K. Dilute (d) coat colour mutation of DBA/2J mice is associated with the site of integration of an ecotropic MLV genome. Nature 293: 370-374, 1981. [PubMed: 6268990] [Full Text: https://doi.org/10.1038/293370a0]
Keeler, C. E. The inheritance of a retinal abnormality in white mice. Proc. Nat. Acad. Sci. 10: 329-333, 1924. [PubMed: 16576828] [Full Text: https://doi.org/10.1073/pnas.10.7.329]
Khramtsov, N. V., Feshchenko, E. A., Suslova, V. A., Shmukler, B. E., Terpugov, B. E., Rakitina, T. V., Atabekova, N. V., Lipkin, V. M. The human rod photoreceptor cGMP phosphodiesterase beta-subunit: structural studies of its cDNA and gene. FEBS Lett. 327: 275-278, 1993. [PubMed: 8394243] [Full Text: https://doi.org/10.1016/0014-5793(93)81003-i]
Lem, J., Flannery, J. G., Li, T., Applebury, M. L., Farber, D. B., Simon, M. I. Retinal degeneration is rescued in transgenic rd mice by expression of the cGMP phosphodiesterase beta subunit. Proc. Nat. Acad. Sci. 89: 4422-4426, 1992. [PubMed: 1350091] [Full Text: https://doi.org/10.1073/pnas.89.10.4422]
McKusick, V. A. The effect of lithium on the electrocardiogram of animals and relation of this effect to the ratio of the intracellular and extracellular concentrations of potassium. J. Clin. Invest. 33: 598-610, 1954. [PubMed: 13152200] [Full Text: https://doi.org/10.1172/JCI102931]
McLaughlin, M. E., Ehrhart, T. L., Berson, E. L., Dryja, T. P. Mutation spectrum of the gene encoding the beta subunit of rod phosphodiesterase among patients with autosomal recessive retinitis pigmentosa. Proc. Nat. Acad. Sci. 92: 3249-3253, 1995. [PubMed: 7724547] [Full Text: https://doi.org/10.1073/pnas.92.8.3249]
McLaughlin, M. E., Sandberg, M. A., Berson, E. L., Dryja, T. P. Recessive mutations in the gene encoding the beta-subunit of rod phosphodiesterase in patients with retinitis pigmentosa. Nature Genet. 4: 130-134, 1993. [PubMed: 8394174] [Full Text: https://doi.org/10.1038/ng0693-130]
Pittler, S. J., Baehr, W. Identification of a nonsense mutation in the rod photoreceptor cGMP phosphodiesterase beta-subunit gene of the rd mouse. Proc. Nat. Acad. Sci. 88: 8322-8326, 1991. [PubMed: 1656438] [Full Text: https://doi.org/10.1073/pnas.88.19.8322]
Pittler, S. J., Keeler, C. E., Sidman, R. L., Baehr, W. PCR analysis of DNA from 70-year-old sections of rodless retina demonstrates identity with the mouse rd defect. Proc. Nat. Acad. Sci. 90: 9616-9619, 1993. [PubMed: 8415750] [Full Text: https://doi.org/10.1073/pnas.90.20.9616]
Pozo, M. G., Bravo-Gil, N., Mendez-Vidal, C., Montero-de-Espinosa, I., Millan, J. M., Dopazo, J., Borrego, S., Antinolo, G. Re-evaluation casts doubt on the pathogenicity of homozygous USH2A p.C759F. Am. J. Med. Genet. 167A: 1597-1600, 2015. [PubMed: 25823529] [Full Text: https://doi.org/10.1002/ajmg.a.37003]
Ray, K., Baldwin, V. J., Acland, G. M., Blanton, S. H., Aguirre, G. D. Cosegregation of codon 807 mutation of the canine rod cGMP phosphodiesterase beta gene and rcd1. Invest. Ophthal. Vis. Sci. 35: 4291-4299, 1994. [PubMed: 8002249]
Riess, O., Kozak, C., Van Ommen, G.-J. Report of the fourth international workshop on human chromosome 4 mapping 1996. Cytogenet. Cell Genet. 74: 57-69, 1996. [PubMed: 8893804] [Full Text: https://doi.org/10.1159/000134384]
Riess, O., Noerremoelle, A., Collins, C., Mah, D., Weber, B., Hayden, M. R. Exclusion of DNA changes in the beta-subunit of the c-GMP phosphodiesterase gene as the cause for Huntington's disease. Nature Genet. 1: 104-108, 1992. [PubMed: 1338767] [Full Text: https://doi.org/10.1038/ng0592-104]
Riess, O., Noerremoelle, A., Weber, B., Musarella, M. A., Hayden, M. R. The search for mutations in the gene for the beta subunit of the cGMP phosphodiesterase (PDEB) in patients with autosomal recessive retinitis pigmentosa. Am. J. Hum. Genet. 51: 755-762, 1992. [PubMed: 1329504]
Sanges, D., Comitato, A., Tammaro, R., Marigo, V. Apoptosis in retinal degeneration involves cross-talk between apoptosis-inducing factor (AIF) and caspase-12 and is blocked by calpain inhibitors. Proc. Nat. Acad. Sci. 103: 17366-17371, 2006. [PubMed: 17088543] [Full Text: https://doi.org/10.1073/pnas.0606276103]
Sidman, R. L., Green, M. C. Retinal degeneration in the mouse. J. Hered. 56: 23-29, 1965. [PubMed: 14276177] [Full Text: https://doi.org/10.1093/oxfordjournals.jhered.a107364]
Suber, M. L., Pittler, S. J., Qin, N., Wright, G. C., Holcombe, V., Lee, R. H., Craft, C. M., Lolley, R. N., Baehr, W., Hurwitz, R. L. Irish setter dogs affected with rod/cone dysplasia contain a nonsense mutation in the rod cGMP phosphodiesterase beta-subunit gene. Proc. Nat. Acad. Sci. 90: 3968-3972, 1993. [PubMed: 8387203] [Full Text: https://doi.org/10.1073/pnas.90.9.3968]
Thaung, C., West, K., Clark, B. J., McKie, L., Morgan, J. E., Arnold, K., Nolan, P. M., Peters, J., Hunter, A. J., Brown, S. D. M., Jackson, I. J., Cross, S. H. Novel ENU-induced eye mutations in the mouse: models for human eye disease. Hum. Molec. Genet. 11: 755-767, 2002. [PubMed: 11929848] [Full Text: https://doi.org/10.1093/hmg/11.7.755]
Tsang, S. H., Woodruff, M. L., Jun, L., Mahajan, V., Yamashita, C. K., Pedersen, R., Lin, C.-S., Goff, S. P., Rosenberg, T., Larsen, M., Farber, D. B., Nusinowitz, S. Transgenic mice carrying the H258N mutation in the gene encoding the beta-subunit of phosphodiesterase-6 (PDE6B) provide a model for human congenital stationary night blindness. Hum. Mutat. 28: 243-254, 2007. [PubMed: 17044014] [Full Text: https://doi.org/10.1002/humu.20425]
Van Gelder, R. N., Wee, R., Lee, J. A., Tu, D. C. Reduced pupillary light responses in mice lacking cryptochromes. Science 299: 222 only, 2003. [PubMed: 12522242] [Full Text: https://doi.org/10.1126/science.1079536]
Weber, B., Collins, C., Kowbel, D., Riess, O., Hayden, M. R. Identification of multiple CpG islands and associated conserved sequences in a candidate region for the Huntington disease gene. Genomics 11: 1113-1124, 1991. [PubMed: 1838348] [Full Text: https://doi.org/10.1016/0888-7543(91)90039-h]
Weber, B., Riess, O., Hutchinson, G., Collins, C., Lin, B., Kowbel, D., Andrew, S., Schappert, K., Hayden, M. R. Genomic organization and complete sequence of the human gene encoding the beta-subunit of the cGMP phosphodiesterase and its localisation to 4p16.3. Nucleic Acids Res. 19: 6263-6268, 1991. [PubMed: 1720239] [Full Text: https://doi.org/10.1093/nar/19.22.6263]
Zeiss, C. J., Johnson, E. A. Proliferation of microglia, but not photoreceptors, in the outer nuclear layer of the rd-1 mouse. Invest. Ophthal. Vis. Sci. 45: 971-976, 2004. [PubMed: 14985319] [Full Text: https://doi.org/10.1167/iovs.03-0301]
Zeiss, C. J., Neal, J., Johnson, E. A. Caspase-3 in postnatal retinal development and degeneration. Invest. Ophthal. Vis. Sci. 45: 964-970, 2004. [PubMed: 14985318] [Full Text: https://doi.org/10.1167/iovs.03-0439]
Zhao, L., Zabel, M. K., Wang, X., Ma, W., Shah, P., Fariss, R. N., Qian, H., Parkhurst, C. N., Gan, W.-B., Wong, W. T. Microglial phagocytosis of living photoreceptors contributes to inherited retinal degeneration. EMBO Molec. Med. 7: 1179-1197, 2015. [PubMed: 26139610] [Full Text: https://doi.org/10.15252/emmm.201505298]